Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.
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Confocal microscopy was supported in part by the Baylor College of Medicine IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. https://www.nichd.nih.gov. JJ was supported by National Institutes of Health GM079684 http://www.nih.gov. MTL was supported by Baylor College of Medicine Cancer Center grant P30 CA125123, National Institutes of Health/National cancer institute grant U54 CA149196 http://www.cancer.gov and Breast Cancer SPORE P50 CA50183 http://trp.cancer.gov/spores/breast. AKG was supported by National Institutes of Health DC010987 nidcd.nih.gov. MW was supported by National Institute of Child Health and Human Development P01 HD22486 https://www.nichd.nih. and National Institute on Deafness and Other Communication Disorders R01 DC004186 http://www.nidcd.nih.gov. HJB was supported by Howard Hughes Medical Institute http://www.hhmi.org/scientists/hugo-j-bellen, Friedreich's Ataxia Research Alliance http://www.curefa.org/index.php and Target ALS http://www.targetals.org/index.html.
Li, Tongchao; Fan, Junkai; Blanco-Sánchez, Bernardo; Giagtzoglou, Nikolaos; Lin, Guang; Yamamoto, Shinya; Jaiswal, Manish; Chen, Kuchuan; Zhang, Jie; Wei, Wei; Lewis, Michael T.; Groves, Andrew K.; Westerfield, Monte; Jia, Jianhang; and Bellen, Hugo J., "Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 Through Poly-Ubiquitination" (2016). Markey Cancer Center Faculty Publications. 71.
S1 Fig. Hh signaling is defective in the ubr3 complementation group.
journal.pgen.1006054.s002.TIF (4760 kB)
S2 Fig. Subcellular localization of Ubr3.
journal.pgen.1006054.s003.TIF (3786 kB)
S3 Fig. Cos2 and Cul1 are up-regulated in ubr3 mutant cells.
journal.pgen.1006054.s004.TIF (2239 kB)
S4 Fig. ubr3b1250 and ubr3b1251 mutants produce truncated, non-functional Ubr3 proteins.
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S5 Fig. ubr3 is required for Hedgehog (Hh) signaling in zebrafish.
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S6 Fig. Ubr3 regulates Cos2 in the wing discs.